{
  "id": "immune-checkpoint-inhibitor",
  "title": "Immune Checkpoint Inhibitor",
  "lang": "en",
  "source_lang": "en",
  "summary": "Immune checkpoint inhibitors are drugs, mostly antibodies, that block inhibitory receptors such as CTLA-4 and PD-1 to reactivate T cells against cancer.",
  "category": "health",
  "subcategory": "drugs",
  "type": "concept",
  "aliases": [
    "immune checkpoint blockade",
    "checkpoint inhibitor",
    "ICI",
    "immune checkpoint blockade therapy"
  ],
  "generated_at": "2026-10-15",
  "model": "pro/claude-haiku-5-5",
  "url": "https://aiwiki.page/en/immune-checkpoint-inhibitor/",
  "translations": {
    "zh-Hans": {
      "url": "https://aiwiki.page/zh/immune-checkpoint-inhibitor/",
      "json": "https://aiwiki.page/zh/immune-checkpoint-inhibitor.json"
    }
  },
  "sections": [
    {
      "heading": "",
      "text": "Immune checkpoint inhibitors (ICIs) are a class of drugs, most of them monoclonal antibodies, that block inhibitory receptors on T cells known as immune checkpoints. These receptors normally limit the strength and duration of immune responses and help maintain self-tolerance. Tumors can exploit the same brakes to escape immune attack, and blocking CTLA-4, PD-1 or PD-L1 releases those brakes. This makes ICIs a central form of cancer immunotherapy and a standard treatment for a growing number of cancers.\n\nThe field rests on basic immunology developed over several decades. Work on CTLA-4 and PD-1 by James Allison and Tasuku Honjo was recognized by the 2018 Nobel Prize in Physiology or Medicine, and the 2025 Nobel Prize extended the foundation to peripheral immune tolerance and regulatory T cells. ICIs have produced durable remissions in a subset of patients with advanced disease, but they also cause immune-mediated side effects that can affect nearly any organ. Their clinical use therefore depends on careful patient selection, biomarker research, and organ-specific management of toxicity.\n\nThe entry proceeds from the biology of immune checkpoints, through the molecular mechanisms of CTLA-4 and PD-1 pathways and the drug classes that target them, to the history of their development, their clinical applications, and the problems of predicting response and overcoming resistance. It then covers immune-related adverse events and their management, and ends with newer strategies and unresolved questions."
    },
    {
      "heading": "Immune checkpoints and the regulation of T cells",
      "text": "Co-stimulation, co-inhibition and the activation threshold\n\nA naive T cell needs more than recognition of an antigen displayed through its T-cell receptor. A second input, co-stimulation, is supplied mainly when CD28 on the T cell meets CD80 and CD86 on antigen-presenting cells. Inhibitory receptors push in the opposite direction, and the net sum of these signals determines how readily a T cell responds. Checkpoint receptors form the braking arm of this system. They limit the size and length of an immune response once a threat is controlled, which helps maintain peripheral tolerance and limits collateral damage to tissue. Under physiological conditions, the interaction between PD-1 and PD-L1 maintains peripheral tolerance and prevents tissue damage from excessive immune responses.\n\nLessons from knockout mice\n\nGenetic studies in mice made the regulatory role of CTLA-4 unusually clear. Mice lacking CTLA-4 developed a fatal lymphoproliferative disease, with lymph nodes and spleens accumulating T cell blasts with up-regulated activation markers, and these blast cells also infiltrating liver, heart, lung, and pancreas tissue. The mice invariably became moribund by 3 to 4 weeks of age. Mutant T cells proliferated spontaneously, although they were also prone to death signals such as Fas cross-linking, leading the authors to conclude that CTLA-4 acts as a negative regulator of T cell activation and is vital for the control of lymphocyte homeostasis. Further work showed that CTLA-4 regulates CD28-dependent peripheral activation of CD4+ T cells, and that the B7 ligands act redundantly, since either B7-1 or B7-2 alone can cause the CTLA-4−/− phenotype.\n\nThe timing of CTLA-4 loss also mattered. Deleting CTLA-4 only in regulatory T cells was sufficient to produce lymphoproliferation and autoimmune diseases including myocarditis, which is fatal at around 8 wk of age. By contrast, deletion in adult mice caused spontaneous lymphoproliferation, hypergammaglobulinemia, and histologically evident pneumonitis, gastritis, insulitis, and sialadenitis, and in contrast to congenital deficiency, this was not fatal. These findings link checkpoint receptors to the prevention of autoimmunity and to the maintenance of immune homeostasis.\n\nCheckpoints as intrinsic regulators that tumours exploit\n\nThe checkpoint concept rests on the observation that normal immune cells carry built-in inhibitory mechanisms that can be turned against the host. PD-1 is highly expressed by activated T cells, B cells, dendritic cells, and natural killer cells, whereas PD-L1 is expressed on several types of tumor cells. When this axis is engaged, this axis is frequently activated through upregulation of PD-L1 on cancer cells, causing T cell dysfunction and tumor immune escape. Tumour-associated inflammation can further raise PD-L1 expression; one review concludes that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking. The same review lists other checkpoint-like pathways that tumours can induce, including galectin-9/TIM-3, IDO1, LAG-3, and CTLA4. This dual role, as physiological brake and as tumour escape route, underlies the rationale for cancer immunotherapy that blocks these receptors.\n\nOther inhibitory receptors\n\nBeyond CTLA-4 and PD-1, several additional receptors have been characterised. Exhausted T cells in cancer express high levels of inhibitory receptors, including PD-1, CTLA-4, TIM-3, LAG-3, BTLA and TIGIT, as well as show impaired effector cytokine production. LAG-3 is a particularly close relative of CD4: it binds to major histocompatibility complex (MHC) class II molecules with greater affinity than CD4, inhibiting T cell activation by disrupting the association of CD4 with MHC II. TIM-3 has a different ligand profile, and it binds to a variety of ligands, such as galectin-9, phosphatidylserine, and CEACAM1, causing inhibitory signals that reduce T cell activation. TIGIT carries an immunoreceptor tyrosine-based inhibitory motif, and the attachment of TIGIT to ligands activates mechanisms that influence the functionality of immune cells as well as the immune response, resulting in immunosuppression.\n\nThese receptors are generally viewed as complements to the better-studied pathways rather than replacements. Although PD-1 and CTLA-4 were the pioneer inhibitory receptors to be studied in relation to T cell exhaustion, other molecules were demonstrated to complement their function in a lower hierarchical level, apparently enabling the fine-tuning of T cell inhibition. Their co-expression is common in tumours; in cervical cancer, for example, in addition to an increase in PD-1 and TIGIT, the emerging receptors Tim-3, LAG-3 and NKG2A were likewise upregulated. This pattern is the basis for the interest in multiple blockade, since in animal models blockade of PD-1 partially reversed T-cell exhaustion, and multiple blockades of inhibitory receptors enhanced T-cell function more efficiently."
    },
    {
      "heading": "Molecular mechanisms of CTLA-4 and PD-1/PD-L1 signaling",
      "text": "CTLA-4 and the costimulatory receptor CD28 both bind the same two ligands on antigen-presenting cells (APCs), CD80 and CD86. CD80 is a dimer and the higher-affinity ligand, while CD86 is a monomer that binds more weakly to both receptors (CD80 is a dimeric high-affinity ligand and CD86 is a monomeric lower-affinity ligand for both receptors.). CTLA-4 engages both ligands with greater affinity and avidity than CD28 (CTLA-4 interacts with both ligands with higher affinity and avidity than CD28). Published fold-differences vary by assay, from roughly tenfold to over a hundredfold (CTLA-4 has 10–100-times greater affinity; another review gives 10- to 20-fold higher affinity than CD28). Because CTLA-4 occupies ligands that CD28 would otherwise use, it blunts costimulation during priming. Engagement also reduces IL-2 production and lowers IL-2 receptor expression, halting the cell cycle in G1 (CTLA-4 inhibits the lymphocyte activation through the reduction in the production of IL-2 and the decrease in the expression of the IL-2 receptor, stopping the cell cycle in G1 phase.). CTLA-4 is expressed at high levels on regulatory T cells (In health, Tregs express CTLA-4, which binds CD80 and CD86 expressed on APCs.). Two non-exclusive mechanisms have been proposed. In one, CTLA-4 removes ligands from the APC by trans-endocytosis, a cell-extrinsic route (The molecular basis for the cell-extrinsic mechanism of CTLA-4 is the trans-endocytosis of two ligands (CD80 and CD86) from the surface of the APC to inside the T cell). In the other, signals acting directly on the T cell, or relayed through dendritic cells, restrain activation, proliferation and cytokine output (The signal of CTLA-4, directly and via DCs, inhibits T-cell activation, proliferation, and cytokine production).\n\nIntracellular trafficking of CTLA-4\n\nMost CTLA-4 sits inside the cell, and only small amounts reach the surface at any given time (Only small amounts of the co-receptor can be detected on the cell surface at any given time, even when optimally expressed following T-cell activation.). Newly synthesized molecules are delivered to the plasma membrane, then internalized quickly and sent toward lysosomal degradation unless further stimulus arrives (newly synthesized CTLA-4 is released to the plasma membrane, rapidly internalised and targeted to lysosomal compartments where it is degraded without further stimulus.). Several proteins, including TRIM, PLD, ARF-1 and TIRC7, have been implicated in transporting CTLA-4 to the surface (several signalling molecules such as Trim, PLD, ARF-1 and TIRC7 have been described to be involved in the transport of CTLA-4 to the cell surface.). Surface retention also depends on phosphorylation of tyrosine 201 within the YVKM motif, which is favored by Src-family kinases such as Lck or Fyn and reduces binding to the adaptor AP-2 (the phosphorylation of Y201 by src kinases such as Lck or Fyn allows for PI3K or SHP-2 binding and prevents the interaction with AP-2, which promotes CTLA-4 surface retention.). On T-cell activation, cytoplasmic CTLA-4 moves toward the immunological synapse, and its accumulation there is governed by TCR signal strength (Its accumulation at the IS is regulated by the strength of TcR signalling.). Because small shifts in surface density alter the balance between stimulation and inhibition, defects in this machinery are clinically relevant; LRBA deficiency, for example, causes marked autoimmunity in humans (Defects in CTLA-4 trafficking due to LRBA deficiency cause profound autoimmunity in humans.).\n\nPD-1 signaling through SHP2\n\nPD-1 is engaged by PD-L1 or PD-L2 on the partner cell. Once ligated, its cytoplasmic ITIM and ITSM motifs are phosphorylated and recruit SHP2 (Upon PD-L1 binding to PD-1, phosphorylation of tyrosine residues in the ITSM and ITIM domains of the PD-1 cytoplasmic region occurs, recruiting and activating SHP2.). Ligated PD-1 molecules cluster into microclusters that sit alongside TCRs and CD28 (tens of PD-1 molecules cluster together after binding their ligand, PD-L1, and form PD-1 microclusters at the same region of TCRs, accompanied by recruitment of the phosphatase SHP2.). SHP2 then dephosphorylates CD3 and ZAP70 components of the signaling complex, which lowers TCR output and IL-2 secretion (activated SHP-2 dephosphorylates TCR-associated CD3 and ZAP70 signalosomes, further attenuating TCR downstream signaling intensity and cytokine secretion such as IL-2). Some studies suggest that CD28 is the preferred substrate, so PD-1 may act mainly by disabling costimulation (the coreceptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1- recruited Shp2 phosphatase.). This view is not uniform: in chronic viral infection, SHP-2 has been reported to be dispensable for T-cell exhaustion and PD-1 signaling (under chronic viral infections, SHP-2 is dispensable for T cell exhaustion and PD-1 signaling). PD-1 signaling also restrains the downstream pathways that sustain glycolysis, thereby shifting T-cell metabolism away from it (PD-1 can influence glycolysis and other metabolic pathways by inhibiting the downstream signal transduction of T cell signaling molecules).\n\nNon-redundancy of the two pathways\n\nCTLA-4 and PD-1 act at different points in the immune response. CTLA-4 acts mainly during priming in lymphoid tissue, where it limits the expansion of newly activated T cells. PD-1 acts mainly later, in peripheral tissues and the tumor microenvironment, where it restrains effector T cells that are already present. Because each checkpoint governs a different stage, blocking both can release more of the response than blocking either alone, which is the basis for combination immunotherapy."
    },
    {
      "heading": "Drug classes, agents and pharmacological features",
      "text": "Agents by target\n\nMost checkpoint inhibitors are monoclonal antibodies directed at three molecules: CTLA-4 on T cells, PD-1 on activated lymphocytes, and PD-L1 on tumor and other cells. Ipilimumab, an anti-CTLA-4 antibody, was the first to be approved, in 2011. Six additional checkpoint-protein-blocking antibodies, all targeting the PD-1/PD-L1 axis, have since been approved by the FDA. The anti-PD-1 group comprises nivolumab, pembrolizumab and cemiplimab; the anti-PD-L1 group comprises atezolizumab, avelumab and durvalumab.\n\nThe targets differ in where they act. Anti-PD-1 agents block the receptor on T cells, whereas anti-PD-L1 agents bind the ligand on tumor cells and antigen-presenting cells, preventing the interaction between PD-1 and PD-L1. Anti-CTLA-4 therapy is positioned differently. Ipilimumab was initially approved as monotherapy for unresectable or metastatic melanoma, and later as adjuvant monotherapy for patients with completely resected cutaneous melanoma with lymph node involvement. Its main current role is in combination with PD-1 blockade. Ipilimumab plus nivolumab was approved for advanced melanoma based on CheckMate 067, which showed significantly improved progression-free survival compared with either agent alone. The combination carries more toxicity, with grade 3 or 4 treatment-related adverse events reported in 16%, 27% and 55% of patients treated with nivolumab alone, ipilimumab alone, or combination therapy, respectively.\n\nIsotype and Fc-mediated effects\n\nThe antibody isotype determines Fc-receptor binding, which has become a central point in the debate over Treg depletion. Ipilimumab has an IgG1 isotype with affinity towards FcγRI, FcγRIIa/b and FcγRIIIa. Tremelimumab is an IgG2 antibody with less affinity towards FcγRs than ipilimumab. Relatlimab, discussed below, is an IgG4 antibody.\n\nMouse studies have supported a model in which antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. In human tumors, however, the picture is less clear. Quantitative immunohistochemistry has found that anti-CTLA-4 immunotherapy using ipilimumab or tremelimumab did not deplete Foxp3+ cells in human tumors. In patients, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism, and one analysis suggested that such activity only appeared relevant in the context of inflamed tumors. Proposed explanations include high expression of the inhibitory receptor FcγRIIB in tumors, which blocking in humanized mice rescued the Treg-depleting capacity and antitumor activity of ipilimumab. Fc-independent activity has also been reported, since a non-Fc receptor binding version of ipilimumab (Ipi-LALAPG) also demonstrated anti-tumor activity in the absence of Treg depletion. The relative contribution of Fc effects and blockade of CD80/CD86 interactions therefore remains unresolved.\n\nDosing, administration and pharmacokinetics\n\nAll approved checkpoint antibodies are given by intravenous infusion, with pembrolizumab, for example, administered as an intravenous infusion over 30 minutes. Labeled schedules are typically flat (fixed-dose) regimens rather than weight-based dosing, and they are set by the long serum half-lives of these immunoglobulins, usually measured in weeks. This allows intervals of two to six weeks. Commonly used schedules include nivolumab 240 mg every two weeks or 480 mg every four weeks, pembrolizumab 200 mg every three weeks or 400 mg every six weeks, cemiplimab 350 mg every three weeks, and atezolizumab 1200 mg every three weeks. Schedules vary by indication and have been revised over time, so current prescribing information should be consulted. Pharmacokinetic data also underpin the choice of schedule in combination regimens, where the two agents may be given on different cycles.\n\nNewer agents: LAG-3, TIM-3, TIGIT and bispecifics\n\nThe LAG-3 inhibitor relatlimab is the most advanced of the newer agents. On 18 March 2022, the U.S. FDA approved the fixed-dose combination of relatlimab developed by Bristol Myers Squibb with nivolumab, under the brand name Opdualag for unresectable or metastatic melanoma. The recommended dose is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks until disease progression or unacceptable toxicity occurs. In the phase 2/3 RELATIVITY-047 trial, median PFS was 10.1 months in the Opdualag arm and 4.6 months in the nivolumab arm, but the final analysis of OS was not statistically significant. The European Commission later approved the combination for tumors with PD-L1 expression below 1%. In the adjuvant setting, LAG-3 inhibition did not lead to the same improved efficacy outcomes seen in advanced melanoma.\n\nAntibodies against TIM-3 and TIGIT, along with bispecific antibodies that engage two checkpoint or immune targets at once, are generally still in clinical investigation. Several phase 3 TIGIT programs have not shown benefit, and the clinical role of TIM-3 blockade is not yet established."
    },
    {
      "heading": "Discovery and development history",
      "text": "Discovery of CTLA-4 and PD-1\n\nThe two receptors that anchor this field were identified in different laboratories, and their roles as inhibitors emerged from separate lines of work. In 1996, James P. Allison and colleagues showed that antibodies against CTLA-4, a cell-surface molecule on T cells, could rouse an immune response strong enough to cure mice bearing tumours. In 1996, James P. Allison and coworkers used this accumulated knowledge to demonstrate that antibodies directed against a cell surface molecule on T cells, CTLA-4, is capable of unleashing an immune response, which cured mice from tumors. Those experiments built on decades of basic immunology, which is why cancer immunotherapy is often described as the product of many laboratories rather than of a single discovery.\n\nPD-1 has an earlier and more unusual origin. Tasuku Honjo's group at Kyoto University reported the molecule in 1992 while examining cell death. Programmed death–1 (PD-1) was discovered in 1992 by T. Honjo and colleagues in Kyoto University as an apoptosis-associated gene. Overexpressing the gene did not itself trigger apoptosis, and later work from the same group showed that PD-1 is induced by antigen-receptor signalling and limits immune responses. Later studies from the same group identified that PD-1 expression was induced through signaling by antigen receptors of T and B lymphocytes and was involved in the inhibition of immune responses, as PD-1–deficient mice developed autoimmune phenotypes.\n\nThe ligand for PD-1 followed a parallel path. PD-L1 was identified in 1999 through molecular cloning, and within a year the Freeman, Wood and Honjo laboratories showed that it binds PD-1 and functions as its partner. In 1999, the B7 homolog one (B7-H1, also called programmed death-ligand 1 [PD-L1]) was identified independently from PD-1 using molecular cloning and human expressed-sequence tag database searches. These two independent lines of studies merged one year later when Freeman, Wood and Honjo's laboratories showed that B7-H1 is a binding and functional partner of PD-1.\n\nAllison and Honjo were jointly recognised by the Nobel Assembly in 2018 for the Nobel citation's phrase \"discovery of cancer therapy by inhibition of negative immune regulation.\" The 2018 Nobel Prize in Physiology or Medicine is awarded to James P. Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation. The prize followed the first wave of approvals and marked the point at which the concept was widely accepted as a therapeutic principle.\n\nFirst approval: ipilimumab in melanoma\n\nAllison's concept was carried into the clinic with industry support. With the aid of biomedical companies Allison succeeded in developing the new concept with anti-CTLA-4 into clinical therapy for patients with advanced forms of melanoma. The pivotal study, phase III trial MDX010-20, enrolled patients whose melanoma had progressed after prior therapy. In that trial, the median survival period for patients receiving ipilimumab plus gp100 was 10 months, compared with 6.4 months for those receiving gp100 alone. The median survival for participants receiving ipilimumab alone was 10.1 months.\n\nOn March 25, 2011, the US Food and Drug Administration approved ipilimumab for previously treated metastatic melanoma. It is the first drug approved for metastatic, or advanced, melanoma in more than a decade. The agency described it as the first agent ever proven to improve survival in advanced melanoma. The European Medicines Agency granted a conditional approval in 2011 limited to pretreated patients. This was the first phase III trial to show a substantial improvement in OS in patients with refractory metastatic melanoma and led to FDA approval of ipilimumab (for all patients with metastatic melanoma) in the USA and European Medicines Agency (EMA) approval (for pretreated patients only) in Europe, in 2011. Some regulatory documents give 2010 as the approval year, reflecting the earlier priority review. Its Biologics License Application was granted priority review designation in August 2010. The recommended dose was 3 mg/kg. The FDA recommended dose for ipilimumab in the advanced setting is 3 mg/kg.\n\nExpansion to anti-PD-1 and anti-PD-L1 agents\n\nAnti-PD-1 and anti-PD-L1 antibodies entered the clinic later but spread faster. Animal work had already suggested that blocking PD-1 could hinder tumour growth. In preclinical studies, Honjo and others showed that PD-1 blockade was a promising strategy in the fight against cancer. A 2012 human study then provided the decisive signal. In 2012, a key clinical study demonstrated obvious efficacy of anti-PD-1 antibody in cancer patients. This treatment led to long-term remission and a possible cure for multiple patients with metastatic cancer. Subsequent approvals of PD-1 and PD-L1 antibodies, including nivolumab and pembrolizumab for melanoma in 2014, were followed by approvals across many tumour types. The use of antibodies directed against PD-1 and its ligand PD-L1 has now been approved for several cancer forms and this treatment is even more efficacious. Combination strategies followed quickly, with the best clinical results have so far been obtained by combining treatment with anti-CTLA-4 and anti- PD-1.\n\nFrom single-agent melanoma trials to randomized programs\n\nEarly development relied heavily on melanoma, where survival benefit was easiest to demonstrate. Over time, development shifted toward large randomized phase III trials in other tumours. The work done by Allison, Honjo, together with many others, have opened up a new avenue for cancer immunotherapy, which led to approval by the authorities for the use of immune checkpoint blockade to treat at least ten types of cancers so far, and many more to come. Those later programmes included lung, kidney and bladder cancers, among others.\n\nRandomized designs also extended the question from advanced to earlier disease. In the phase III EORTC 18071 trial, 951 patients with stage III cutaneous melanoma who had adequate resection of lymph nodes were randomized to adjuvant ipilimumab or placebo. Adjuvant ipilimumab at a 10 mg/kg dose reduced the risk of recurrence by 25% versus placebo. The FDA later expanded the label to cover this adjuvant setting, at a dose higher than that used in advanced disease. The drug was approved at this 10 mg/kg dose, which is higher than the 3 mg/kg dose the FDA recommended in ipilimumab's initial approval for advanced melanoma.\n\nRegulatory mechanisms also shaped the pace of approvals. Priority review and related expedited pathways allowed agents with strong survival data to reach patients sooner, and the adjuvant ipilimumab approval illustrates how a supplemental application could extend an established drug into a new clinical setting. The field's transition from a handful of melanoma trials to broad, multi-tumour randomized testing set the template for later checkpoint inhibitors."
    },
    {
      "heading": "Clinical applications across tumor types",
      "text": "Melanoma\n\nMelanoma has the most mature evidence base for checkpoint blockade. The phase 3 CheckMate 067 trial now has a minimum of ten years of follow-up. At that point, ten-year overall survival rates were 43%, 37%, and 19% with nivolumab/ipilimumab, nivolumab monotherapy, and ipilimumab monotherapy, respectively. The gap between arms is therefore wide, but only a minority of patients on ipilimumab were alive at this landmark. For the combination, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 when the combination was compared with ipilimumab.\n\nLong-term control is concentrated in patients who respond early. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab. Earlier pooled analyses of ipilimumab trials had already described a survival plateau that was independent of prior therapy or ipilimumab dose.\n\nNon-small cell lung cancer\n\nThe most rapid recent expansion has occurred in resectable disease. CheckMate 816 randomly assigned 358 patients with resectable NSCLC to receive either nivolumab plus platinum-doublet or platinum-doublet chemotherapy alone for three cycles before planned surgical resection. Its primary endpoint was event-free survival, and the approval was granted on that basis. On March 4, 2022, nivolumab received FDA regular approval, based on the CheckMate 816 trial results, for use with platinum-doublet chemotherapy in resectable NSCLC in the neoadjuvant setting.\n\nKEYNOTE-671 extended this approach to pembrolizumab. Patients received cisplatin-based chemotherapy with pembrolizumab or placebo before surgery and then up to a year of adjuvant treatment. Compared with neoadjuvant chemotherapy alone, adding perioperative pembrolizumab was associated with a significant improvement in EFS (HR 0.58). KEYNOTE-671 was the first perioperative ICI study to lead to FDA approval for this indication, in October 2023, and it was also the first phase 3 trial to show a significant overall survival improvement with the perioperative approach. Adjuvant pembrolizumab and atezolizumab are also approved for operable disease, based on the PEARLS and Impower010 trials, respectively. Across these studies, stage III patients tend to gain the most from the addition of a checkpoint inhibitor. Critics have questioned whether pathological response and event-free survival are validated surrogates in this setting, and whether the CheckMate 816 control arm reflected routine practice.\n\nOther solid tumors and hematologic malignancies\n\nCheckpoint inhibitors are established in several other settings, although these are less often discussed in trial-level detail. In renal cell carcinoma, nivolumab with ipilimumab (CheckMate 214) and pembrolizumab with axitinib were approved first-line, and adjuvant pembrolizumab followed. In urothelial carcinoma, atezolizumab, nivolumab, pembrolizumab, durvalumab and avelumab (the latter as maintenance) are used, and first-line pembrolizumab combined with enfortumab vedotin was approved in 2023. Recurrent or metastatic head and neck squamous cell carcinoma is treated with pembrolizumab or nivolumab, with first-line pembrolizumab plus platinum and fluorouracil. Avelumab was the first agent approved for metastatic Merkel cell carcinoma, and nivolumab and pembrolizumab are used for relapsed or refractory classical Hodgkin lymphoma.\n\nMSI-high colorectal cancer\n\nMSI-high or mismatch repair-deficient colorectal cancer has been a notable case where biomarker-defined eligibility led to new first-line options. The FDA approved nivolumab with ipilimumab for adult and pediatric patients aged 12 years and older with unresectable or metastatic MSI-H or dMMR colorectal cancer. In the first-line CheckMate 8HW comparison, the risk of disease progression or death was reduced by 79% with nivolumab/ipilimumab compared with chemotherapy (HR, 0.21). Compared with nivolumab alone, the combination's hazard ratio for progression-free survival was 0.62 across all lines of therapy. The trial continues to assess secondary endpoints such as overall survival.\n\nCombinations and trial design\n\nCombination regimens fall into several groups: dual checkpoint blockade, as in melanoma, renal cell carcinoma and MSI-high colorectal cancer; checkpoint inhibitors with platinum-based chemotherapy, as in NSCLC and urothelial and head and neck cancers; and checkpoint inhibitors with targeted or anti-angiogenic agents, such as pembrolizumab with axitinib. Radiotherapy has been combined with checkpoint inhibitors mainly through consolidation after concurrent chemoradiation in unresectable stage III NSCLC, where durvalumab was approved. Combinations with EGFR-directed tyrosine kinase inhibitors have been constrained by toxicity concerns.\n\nMost of these combinations were established in randomized phase 3 trials comparing the experimental arm with chemotherapy, placebo, or single-agent comparators. Stratification factors such as BRAF status, metastasis stage and PD-L1 expression were built into designs like CheckMate 067, randomization was stratified according to BRAF mutation status, metastasis stage, and programmed death ligand 1 expression. Some indications were first granted on earlier evidence, and the accelerated approval for single-agent nivolumab in MSI-high colorectal cancer was later converted to traditional approval after confirmatory data became available."
    },
    {
      "heading": "Predictive biomarkers and assessment of response",
      "text": "PD-L1 immunohistochemistry is the most widely used predictive test in this field, and it functions as a companion diagnostic for several approved antibodies. Each anti-PD-1/PD-L1 agent has its own companion assay, and these assays have not been standardized or made interchangeable. Cutoffs also depend on the drug and tumor type. For pembrolizumab with the 22C3 assay, the threshold is a tumor proportion score of at least 1% in non-small cell lung cancer, but a combined positive score of at least 10 in esophageal squamous cell carcinoma, while cemiplimab in the same lung setting uses a tumor proportion score of at least 50%. Even so, three commercially available assays showed overall agreement above 90% in one study of 493 non-small cell lung cancer samples.\n\nThe predictive limits of PD-L1 are substantial. In tumors that respond well to anti-PD-1 agents, such as melanoma, renal cell carcinoma, lung cancer and bladder cancer, PD-L1 expression on tumor cells ranges from 14% to 100%, which weakens its power to separate responders from non-responders. The predictive value of PD-L1 staining in melanoma has been questioned because of inconsistent correlation with clinical outcome. Some indications do not require a test at all; for nivolumab in certain settings, test results are not required for drug use. Tissue sampling is a further constraint, since a valid assessment needs an adequate tumor sample, and the specimen must contain at least 100 viable, invasive tumor cells for one commercial test.\n\nTumor mutational burden (TMB), mismatch repair deficiency (dMMR) and microsatellite instability (MSI-H) are tissue-agnostic markers, meaning they are applied across histological types. Mismatch-repair-deficient tumors tend to be hypermutated, and tumors with high TMB present higher numbers of neoantigens that can potentially activate antitumor immunity. The FDA granted pembrolizumab approval for unresectable or metastatic MSI-H or dMMR solid tumors on May 23, 2017, and this was the first tissue-agnostic approval, based on demonstration of a clinically meaningful objective response rate. Dostarlimab later received a dMMR indication in 2021. TMB followed in June 2020, when the approval of pembrolizumab for TMB-high cancers was the first time the FDA approved a cancer treatment for an indication based on TMB. The evidence rested largely on an exploratory analysis of KEYNOTE-158, in which the objective response rate was 29% in TMB-high tumors and 6% in non-TMB-high tumors. Experts have questioned solely using TMB, at a cutoff of 10 mutations per megabase, as a predictive marker for all solid tumors. Assay choice matters as well, since approximately 10–11% of patients were potentially misclassified by panel-based methods compared with whole-exome sequencing in one cohort.\n\nTumor-infiltrating lymphocytes, gene expression signatures, including those reflecting interferon-γ activity, and on-treatment dynamic markers such as changes in circulating tumor DNA or blood-based immune measurements are being studied as complements to static markers such as PD-L1 and TMB. These approaches have not yet been incorporated into routine selection of patients, and their predictive value is still being defined in prospective clinical trials.\n\nAtypical response patterns complicate the interpretation of imaging. Pseudoprogression was first described in melanoma with the use of cytotoxic T-lymphocyte associated protein 4 inhibitors, and its frequency is generally low, since the rate of pseudoprogression does not exceed 10% in patients treated with immune checkpoint inhibitors. Because conventional RECIST criteria can misclassify it, the immune-specific criteria iRECIST were developed. In cases of new lesions or apparent progression, a follow-up scan after 4-8 weeks is recommended to distinguish between true progression and pseudoprogression. To confirm progression from the unconfirmed category, an additional increase of at least 20% in target lesion burden, worsening of non-target lesions, or new lesions must be observed. At present, no validated clinical or biological markers exist to diagnose pseudoprogression at its first appearance.\n\nHyperprogression, an accelerated tumor growth after treatment initiation, has no single agreed definition. One group used a time to treatment failure under two months, a 50% increase in tumor burden compared with baseline, and a progression pace more than twofold faster, while another used a tumor growth kinetic ratio between on-treatment and baseline values of at least 2. In head and neck cancer, one study reported an HPD rate of 29%, with statistically significantly worse progression-free survival. Genomic analysis has linked the phenotype to MDM2/4 amplification and EGFR alterations, and older age has been proposed as a predictor. Because these definitions differ, reported frequencies are difficult to compare across studies."
    },
    {
      "heading": "Primary and acquired resistance",
      "text": "Tumor-intrinsic mechanisms\n\nClinicians separate two patterns. In primary resistance, resistance is judged by whether an initial response occurred before relapse, so tumors that never respond and tumors that relapse after a response are classed differently. In hepatocellular carcinoma, approximately 40% of patients do not achieve disease control with ICIs because of primary resistance, and a similar proportion experience progression after an initial response caused by secondary resistance.\n\nTumor cells can escape through their own biology. Mutations in genes linked to MHC presentation, such as beta-2 microglobulin, can severely disrupt the antigen-presenting mechanism and produce resistance to ICIs. Homozygous loss or heterozygous mutations combined with loss of heterozygosity in the B2M gene can reduce MHC I expression and confer primary or acquired resistance. Other intrinsic routes include mutations in JAK1 and JAK2, which have been implicated in primary resistance to anti-PD-1 therapy, and the selection of poorly immunogenic tumors that lose neoantigen expression under continuous immune pressure. Activation of stromal and checkpoint-independent signaling also contributes; WNT/β-catenin signaling represses key chemokine genes, reducing recruitment of Batf3-lineage dendritic cells and hence T-cell priming.\n\nCompensatory upregulation of alternative checkpoints\n\nBlocking one inhibitory receptor often prompts T cells to raise others. In a murine ovarian cancer model, blockade of PD-1, LAG-3, or CTLA-4 alone conferred a compensatory upregulation of the other checkpoint pathways, which could be overcome through combinatorial blockade strategies. In head and neck squamous cell carcinoma, nivolumab treatment of tumor-infiltrating lymphocytes led to upregulation of Tim-3 expression, suggesting a circuit of compensatory, cross-talk signaling. The reverse has also been observed: blockade of PD-1 induces the upregulation of CTLA-4 expression in a murine melanoma model and vice versa. Experimental work links TIM-3 induction to the PI3K–Akt pathway Tim-3 upregulation after PD-1 blockade is PI3K/Akt pathway dependent.\n\nThe clinical relevance of these receptors is still being defined. TIM-3+ TILs also correlate with poorer OS and may be considered an independent prognostic factor of poor disease outcome. Preclinical data suggest that treatment with an anti–TIM-3 antibody concurrently with anti–PD-L1 and radiotherapy led to significant tumor growth delay, enhanced T-cell cytotoxicity, decreased Tregs, and improved survival. Acquired resistance has also been linked to T cell exhaustion driven by the up-regulation of other checkpoint inhibitors such as TIM3, LAG3 and VISTA following checkpoint blockade.\n\nImmunosuppressive microenvironment and \"cold\" tumors\n\nResistance is not determined by the tumor cells alone. The cell types include regulatory T-cells (Treg cells), myeloid derived suppressor cells (MDSCs), cancer-associated adipocytes, fibroblasts and endothelial cells; and tumor-associated macrophages (TAMs), and these populations act together within the tumor microenvironment. TAMs, MDSCs, and Tregs reinforce suppression through IL-10, TGF-β, and other mediators, contributing to poor prognosis and therapy resistance.\n\nTwo forms of \"cold\" tumor are commonly distinguished. Immune-excluded tumors contain many lymphocytes at the invasive margin or in fibrous stroma, but few T cells successfully infiltrate into the tumor nests, whereas immune-desert tumors lack significant T cell infiltration anywhere in the tumor or its periphery. Exclusion is considered one of the leading causes of resistance to ICT in cold tumours. Several mechanisms contribute. Cancer cells can influence local TAMs and CAFs to block the infiltration of anti-tumour T cells. Cancer-associated fibroblasts produce dense ECM proteins like collagen and fibronectin, which increase stromal stiffness and create a mechanical barrier preventing T cell migration into the tumor core. Chemokines also matter: IL-8 acts as a potent chemoattractant that drives neutrophil and gMDSC accumulation within tumor stroma. Mutation burden does not fully explain these differences, since tumours with high TMB may still exhibit a lack of response to ICT, indicating the presence of additional immunosuppressive mechanisms.\n\nStrategies proposed to overcome resistance\n\nMost proposals remain at the stage of trials or preclinical models. Emerging data on mechanisms of resistance are derived mainly from either preclinical studies or secondary correlative analyses from clinical trials. Sequencing and biomarker-guided selection are central to current thinking, because improved understanding of the molecular and immunologic mechanisms underlying immunotherapy resistance is essential for developing biomarkers and for guiding the optimum approach to selecting treatment regimens and sequencing. Proposed biomarkers include PD-L1 expression; IFN-γ signature; exhaustion markers (e.g., TOX); multiplex IHC, with dual checkpoint blockade among the actionable strategies.\n\nTargeting the microenvironment is another line of work. Remodeling the extracellular matrix may help: reducing physical and mechanical barriers established by stromal cells can improve T cell infiltration and enhance the effectiveness of checkpoint blockade therapies. In a phase II setting for microsatellite-stable colorectal cancer, tocilizumab (an IL-6 blocker) was combined with atezolizumab, on the premise that IL-6 blockade will reduce MDSCs, increase T-cell infiltration, and convert immunologically \"cold\" tumors toward a more responsive state. A review in Hodgkin lymphoma suggests that targeting these mechanisms in parallel to PD-1 may potentially increase efficiency of PD-1 blockade therapy. Broader frameworks aim to transform cold, immune-excluded tumors into hot, immune-reactive ones."
    },
    {
      "heading": "Immune-related adverse events: mechanisms and profile",
      "text": "Immune-related adverse events (irAEs) are inflammatory toxicities that appear when checkpoint blockade weakens the control that peripheral tolerance normally exerts over self-reactive T cells. The mechanism of irAEs is unclear. Still, the common explanation is that the same immune activation that drives antitumor responses can spill over into healthy tissue. Because all ICIs disrupt immune self-tolerance, autoimmunity can develop against multiple tissues. Target organs span nearly the whole body. Most episodes respond to treatment, but some adverse effects can be serious and lead to permanent illness, and fatal outcomes are uncommon.\n\nReviews group the common presentations into endocrine (thyroid, adrenal, pituitary), cutaneous, GI, hepatic, neurological, and pulmonary events. Other series also report frequent rheumatic involvement. Within this spectrum, colitis, hepatitis, pneumonitis, myocarditis, hypophysitis and thyroid dysfunction are among the most clinically consequential. In a pooled safety dataset of 4,849 patients treated with nivolumab plus ipilimumab, myocarditis occurred in about 1.2% and was fatal in 0.08%, while hypothyroidism (9.9%) and hypophysitis (about 4.2%) were far more common. Treatment-related deaths are rare, and most toxicities resolved with steroid administration or other immunosuppressive treatments.\n\nIncidence and severity depend heavily on the regimen. A meta-analysis of 21 studies with 11,144 patients found that anti-CTLA-4 agents raised the relative risk of several events, notably diarrhea, colitis, pruritus and rash, compared with control therapies. The gastrointestinal predominance is usually linked to the way CTLA-4 blockade stimulates immunity in gut-associated lymphoid tissue. Combination therapy shows the sharpest difference. The incidence of treatment-related AEs of grade 3–4 was substantially higher in the combination arm (59%) than in the nivolumab arm (24%) or the ipilimumab arm (28%). Grade 3–4 colitis followed a similar pattern, occurring in roughly 8% of patients on combination therapy or ipilimumab alone but below 1% on nivolumab alone in a phase III melanoma comparison. In the combination arm of that trial, two deaths were related to the study drug, one from autoimmune myocarditis and one from liver necrosis.\n\nTiming also differs by agent. In a pooled analysis of 22 trials of anti-CTLA-4 therapy, the median time of onset of irAEs was about 10 weeks (IQR, 6–12) after the onset of treatment, corresponding with the first three cycles but varied according to the organ system involved. For PD-1 and PD-L1 agents, the reported figures are less uniform. In one meta-analysis of cutaneous events, the median time of onset of irCAEs was 5.4–20.8 weeks across studies, and other work defines early irAEs as those occurring within two months after the commencement of ICIs. Across ICIs as a whole, the median irAEs onset time ranged from 2.4 to 28 weeks. Because cohorts and methods differ, direct comparison between CTLA-4 and PD-1 onset remains tentative.\n\nSeveral analyses associate the occurrence of irAEs with better outcomes. A meta-analysis of 131 studies reported an association between irAEs occurrence and longer OS (HR, 0.55 [95%CI, 0.51–0.59]). The link was stronger for PD-(L)1 agents, where patients experiencing irAEs had a longer OS (HR, 0.52 [95%CI, 0.47–0.56]), while no comparable association emerged for anti-CTLA-4 therapy. For CTLA-4 blockade, irAE occurrence was associated with clinical response in 60% of patients. These findings are observational and open to bias. Patients must survive long enough to develop irAEs, which can inflate apparent benefit through lead-time and immortal-time effects. Reviews also flag missing information on survival analysis, therapy dechallenge and rechallenge, concomitant therapies, comorbidities, time to onset, and duration of irAEs. No biomarker currently predicts which patients are likely to develop toxicity from ICI therapy."
    },
    {
      "heading": "Management of irAEs and rechallenge decisions",
      "text": "Grading and first-line corticosteroids\n\nOrgan-specific toxicities are staged with the Common Terminology Criteria for Adverse Events, and the initial treatment for most grade 2 or greater toxicities includes immunosuppression with corticosteroids. The ASCO guideline sets out dosing by grade. For grade 2 events, corticosteroids (initial dose of 0.5-1 mg/kg/d of prednisone or equivalent) may be administered, and checkpoint inhibitors are usually held. For grade 3 events, checkpoint inhibitors are stopped and high-dose corticosteroids (prednisone 1-2 mg/kg/d or equivalent) are started, with a taper lasting at least 4-6 weeks. Intravenous methylprednisolone is an accepted alternative at a comparable dose. Prophylaxis against Pneumocystis jirovecii pneumonia should be considered for patients receiving steroids equivalent to more than 20 mg of prednisone daily.\n\nDosing rests on limited evidence. For myocarditis, most guidelines favor pulse-dose intravenous methylprednisolone, whereas ASCO recommends lower-dose prednisone with escalation if needed, and the dosing, duration, and timing of steroids recommended by expert consensus guidelines are based on limited evidence.\n\nSecond-line immunosuppressants\n\nIf symptoms do not improve with 48-72 hours of high-dose steroid, infliximab may be offered for some toxicities. Other agents listed for steroid-refractory disease include vedolizumab, rituximab, cyclophosphamide and mycophenolate. Infliximab is typically given at 5-10 mg/kg for steroid refractory disease. Vedolizumab acts by blocking the α4β7 integrin, so that T cells cannot bind and home into the inflamed bowel mucosa. In a meta-analysis, patients treated with vedolizumab had lower rates of recurrence of colitis as compared to patients on IFX, though these comparisons are observational and carry selection bias. Calcineurin inhibitors have also been used after anti-TNF failure, with one series reporting that 81% of patients who had all failed infliximab responded to calcineurin inhibitors.\n\nChoice of agent depends on the organ involved. In myocarditis, abatacept is the preferred choice for the treatment of isolated steroid-refractory IRM, and infliximab carries a caution in patients with reduced cardiac function. For myositis, plasmapheresis, IVIG, methotrexate, azathioprine, mycophenolate are among the options listed in guidelines. Because these decisions are made case by case, MDT discussion is recommended before restarting ICIs treatment in cases of uncomplicated irAEs, and multidisciplinary input is generally expected in steroid-refractory cases.\n\nHolding, discontinuation and rechallenge\n\nASCO advises that grade 4 toxicities warrant permanent discontinuation of ICPis, except for endocrinopathies that have been controlled by hormone replacement. For grade 2 events, treatment is held and may be resumed when symptoms and/or laboratory values revert to grade 1 or less. Cardiac toxicities are an exception to the general rule that grade 1 events allow continued treatment, and they warrant closer attention even at low grade. Guidelines also state that dose adjustments are not recommended.\n\nRechallenge carries a real risk of recurrence. A pharmacovigilance analysis drawn from VigiBase reported that one hundred thirty recurrences (28.8%; 95% CI, 24.8-33.1) of the initial irAE were observed. Pooled meta-analytic estimates are higher, with pooled incidences for any-grade irAEs ranging from 34.2% to 52.2%, and high-grade (Grade ≥ 3) irAEs from 11.7% to 21.5%. Recurrence varies by organ: colitis, hepatitis and pneumonitis were associated with higher recurrence, whereas adrenal events were associated with lower recurrence rates. Strategy also matters; in one set of de-escalation studies, resumption of anti-PD-(L)1 monotherapy had a higher rate of overall and recurrent irAEs than resumption of anti-CTLA-4 alone. Small retrospective series after grade 3-4 events have reported more favorable outcomes, but their samples are limited.\n\nCardiac, neurologic and endocrine follow-up\n\nCardiac and neurologic irAEs call for rapid evaluation and close monitoring, given their potential severity. Endocrine irAEs are often permanent: because ASCO allows continued checkpoint therapy for endocrinopathies controlled by hormone replacement, long-term replacement therapy is a central part of follow-up, particularly for thyroid and pituitary–adrenal dysfunction. Patients who continue treatment or who are rechallenged therefore need ongoing review of hormone levels and organ function, alongside the monitoring required for any recurrence."
    },
    {
      "heading": "Emerging strategies and unresolved questions",
      "text": "Combination approaches and their stage of testing\n\nMost combination strategies aim to make poorly infiltrated tumours responsive to checkpoint blockade. Oncolytic viruses are the most developed example. Beyond lysing cancer cells, they increase the infiltration of cytotoxic CD8+ T cells into the tumour and can turn a \"cold\" microenvironment into a \"hot\" one Pre-clinical and clinical data have shown that oncolytic vectors can induce anti-tumor immunity and markedly increase immune cell infiltration (including cytotoxic CD8+ T cells) into the local tumor microenvironment. This \"priming\" by the viral infection can change a 'cold' tumor microenvironment into a 'hot' one. Because checkpoint inhibitors work best where lymphocytes are abundant, the virus is viewed as setting the stage for subsequent drug delivery. In a phase Ib study of ipilimumab with the oncolytic virus T-VEC in 19 untreated patients with stage IIIB–IV melanoma, the objective response rate was 50% with no dose-limiting toxicities Ipilimumab (an anti-CTLA-4 antibody) was used with T-VEC in a phase Ib trial that enrolled 19 patients with previously untreated stages IIIB to IV melanoma. The trial results were significant for an objective response rate of 50%, and there were no dose-limiting toxicities.. Trials such as CAPTIVE, CAPRA and Masterkey-265 are testing this approach There are multiple ongoing clinical trials that are currently combining oncolytic viruses with checkpoint inhibitors (e.g. CAPTIVE, CAPRA, and Masterkey-265), and the initial results are encouraging..\n\nCombinations with vaccines, cytokines (such as interleukin-2) and cell therapies are, for the most part, at preclinical or early-phase stages, and their clinical benefit is less established than that of oncolytic viruses. Bispecific antibodies that engage two checkpoint targets, or a checkpoint target and another immunoregulatory pathway, form a further active development area; most of these agents are still being tested, and whether they outperform combinations of approved antibodies remains an open question.\n\nTumours with poor response and the basis of durable benefit\n\nTumours with little T-cell infiltration or heterogeneous PD-L1 expression respond poorly. One review cites objective response rates of 5–8% in such tumours, compared with 30–40% in \"hot\" tumours Immune checkpoint inhibitor (ICI) has limited efficacy in the treatment of immune \"cold\" tumors. Due to insufficient T cell infiltration and heterogeneous programmed death ligand 1 (PD-L1) expression, the ORR is only 5%–8% compared with 30%–40% of \"hot\" tumors.. Proposed remedies therefore centre on reshaping the immunosuppressive microenvironment, for instance through immunogenic cell death and innate immune activation Systematic analysis of mechanistic interactions across tumor types and clinical trial data demonstrates that OVs transform the immunosuppressive microenvironment by inducing immunogenic cell death and activating innate immunity..\n\nDurable responses are documented in a minority of patients. In KEYNOTE-010, 79 of 690 patients completed 2 years of pembrolizumab therapy, and their 2-year progression-free survival after completion was 57.7%. In KEYNOTE-024, 39 patients completed 2 years of pembrolizumab therapy, with the majority (82%) still alive at 5 years. The mechanisms behind this persistence are not settled. Immune memory is a leading hypothesis: a case report suggests that favourable outcomes after rechallenge may reflect it a post-discontinuation ICI rechallenge can still yield favorable outcomes potentially accredited to immune memory., and in a mouse study tumour-specific CD8+ T cells showed a memory phenotype the tumor-specific CD8+ T cells showing a memory phenotype (CD44hi) suggest the effective induction of a potent immune memory response.. Whether these findings translate directly to patients remains to be confirmed.\n\nTreatment duration, discontinuation and dosing\n\nMost trials capped treatment at two years, and the optimal duration is still uncertain. In a retrospective real-world cohort of advanced NSCLC patients whose tumours were controlled after at least 18 months, treatment was stopped by choice of the prescriber and toxicity in 46% and 22% respectively. In a separate survival analysis, patients who continued beyond six or twelve months had longer progression-free and overall survival than those who stopped early Patients who continued treatment had a longer duration of OS compared to those who discontinued treatment at 6 months (33.9 months vs 14.4 months, p= 7.2E-08) and 12 months (39.7 months vs 18.0 months, p= 2.0E-07).. Such observational comparisons are confounded by the reasons for stopping, and a phase III trial in urothelial cancer is directly comparing stopping after about a year with continuation This phase III trial compares survival in urothelial cancer patients who stop immune checkpoint inhibitor treatment after being treated for about a year to those patients who continue treatment with immune checkpoint inhibitors..\n\nDosing is also open to question. Early-phase clinical trials have shown target inhibition and high activity at doses lower than those registered and evaluated in clinical trials. Pharmacokinetic and pharmacodynamic data point the same way, though clinical confirmation is still limited.\n\nCost, access and monitoring\n\nAccess is uneven. Modelling of expanded PD-1/PD-L1 monotherapy in advanced NSCLC projected that at an estimated per-patient lifetime cost of US$37,600–US$75,100, total costs could reach US$14,087 million with fixed dosing, or US$9080 million with weight-based dosing, and its authors judged equitable access in lower-income countries doubtful without substantial price reductions Expanding access to PD1/PD-L1 inhibitors for advanced NSCLC over 10 years demands significant funding, making equitable access in lower-income countries doubtful without a significant price reduction.. Suggested responses include price negotiation, biosimilars, optimised dosing and treatment duration Policymakers should negotiate lower prices to ensure cost-effectiveness and affordability, improve spending efficiency by optimised dosing and treatment duration, and enhance health system capacity, including ensuring appropriate use and introducing biosimilars.. Coverage gaps persist even in wealthier systems, where insured patients may still face substantial out-of-pocket costs, and in some middle-income settings the reported share of patients paying out of pocket is considerable. In Vietnam, minimal reimbursement has made checkpoint inhibitors available to fewer than 1% of eligible patients. Standardised monitoring is also unevenly available: cardiac MRI, which helps establish the diagnosis of checkpoint-inhibitor myocarditis, is less accessible in low- and middle-income countries, a gap that matters more as use expands Even though differential rates of utilisation prevail, this is likely to change going forwards globally, and therefore variation in access to diagnostic tools will become increasingly relevant.. Predictive biomarkers that could guide selection, duration and dosing are still needed."
    }
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  "sources": [
    {
      "title": "Regulation of PD-1 and PD-L1 expression in tumor immune microenvironment - PubMed",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42470994/"
    },
    {
      "title": "Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4",
      "url": "https://www.science.org/doi/10.1126/science.270.5238.985"
    },
    {
      "title": "Lymphoproliferative Disorder in CTLA-4 Knockout Mice Is Characterized by CD28-Regulated Activation of Th2 Responses1",
      "url": "https://academic.oup.com/jimmunol/article-abstract/162/10/5784/8041680?redirectedFrom=fulltext"
    },
    {
      "title": "B7-1 or B7-2 Is Required to Produce the Lymphoproliferative Phenotype in Mice Lacking Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC2192978/"
    },
    {
      "title": "Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood",
      "url": "https://www.pnas.org/doi/10.1073/pnas.1603892113"
    },
    {
      "title": "PD-1/PD-L1 immune checkpoint: Potential target for cancer therapy - PubMed",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30191996/"
    },
    {
      "title": "Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332843/"
    },
    {
      "title": "T-cell exhaustion in the tumor microenvironment",
      "url": "https://www.nature.com/articles/cddis2015162"
    },
    {
      "title": "Targeting T cell exhaustion in colorectal cancer: emerging roles of LAG-3, TIM-3, and TIGIT signaling in overcoming immunotherapy resistance",
      "url": "https://link.springer.com/article/10.1186/s12964-025-02638-6"
    },
    {
      "title": "Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation",
      "url": "https://www.researchgate.net/publication/303304196_Lag-3_Tim-3_and_TIGIT_Co-inhibitory_Receptors_with_Specialized_Functions_in_Immune_Regulation"
    },
    {
      "title": "CD4^+^ T cells from chronic Chagas disease patients with different degrees of cardiac compromise exhibit distinct expression patterns of inhibitory receptors TIGIT, Tim-3 and Lag-3",
      "url": "https://www.biorxiv.org/content/10.1101/694729.full.pdf"
    },
    {
      "title": "T Cell Exhaustion in the Cervical Cancer Tumor Microenvironment: PD-1 Overexpression and Co-Expression with TIGIT, Tim-3, LAG-3, and NKG2A",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12651438/"
    },
    {
      "title": "Screening immunomodulatory agents by CTLA-4 upregulation",
      "url": "https://image-ppubs.uspto.gov/dirsearch-public/print/downloadPdf/7014998"
    },
    {
      "title": "Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4 - ScienceDirect",
      "url": "https://www.sciencedirect.com/science/article/pii/1074761395901256"
    },
    {
      "title": "Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4 - PubMed",
      "url": "https://pubmed.ncbi.nlm.nih.gov/7584144/"
    },
    {
      "title": "Unravelling T cell exhaustion through co‐inhibitory receptors and its transformative role in cancer immunotherapy",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12104568/"
    },
    {
      "title": "CTLA-4: a moving target in immunotherapy - ScienceDirect",
      "url": "https://www.sciencedirect.com/science/article/pii/S0006497120325854"
    },
    {
      "title": "CTLA-4 - an overview",
      "url": "https://www.sciencedirect.com/topics/immunology-and-microbiology/ctla-4"
    },
    {
      "title": "Cytotoxic T Lymphocyte Antigen 4 - an overview",
      "url": "https://www.sciencedirect.com/topics/neuroscience/cytotoxic-t-lymphocyte-antigen-4"
    },
    {
      "title": "Anti-CTLA-4 nanobody as a promising approach in cancer immunotherapy",
      "url": "https://www.nature.com/articles/s41419-023-06391-x"
    },
    {
      "title": "Frontiers",
      "url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1198365/full"
    },
    {
      "title": "Diverse Mechanisms Regulate the Surface Expression of Immunotherapeutic Target CTLA-4",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255484/"
    },
    {
      "title": "CTLA-4 trafficking and surface expression - PMC - NIH",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC4186961/"
    },
    {
      "title": "CTLA-4 trafficking and surface expression: Trends in Immunology",
      "url": "https://www.cell.com/trends/immunology/fulltext/S1471-4906(08)00110-5"
    },
    {
      "title": "Regulation of CTLA‐4 recycling by LRBA and Rab11 - Janman - 2021 - Immunology - Wiley Online Library",
      "url": "https://onlinelibrary.wiley.com/doi/10.1111/imm.13343"
    },
    {
      "title": "Regulatory mechanisms of PD-1/PD-L1 in cancers",
      "url": "https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02023-w"
    },
    {
      "title": "PD-L2 suppresses T cell signaling via coinhibitory microcluster formation and SHP2 phosphatase recruitment",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121797/"
    },
    {
      "title": "T cell co-stimulatory receptor CD28 is a primary target for PD-1–mediated inhibition",
      "url": "https://www.biorxiv.org/content/10.1101/086652v1.full"
    },
    {
      "title": "Quantitative characterization of CTLA4 trafficking and turnover using a combined in vitro and in silico approach",
      "url": "https://www.biorxiv.org/content/10.1101/106898v1.full"
    },
    {
      "title": "Frontiers",
      "url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1340726/full"
    },
    {
      "title": "Molecular Interactions of Antibody Drugs Targeting PD-1, PD-L1, and CTLA-4 in Immuno-Oncology",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470598/"
    },
    {
      "title": "Biomarkers of response to PD-1 pathway blockade",
      "url": "https://www.nature.com/articles/s41416-022-01743-4"
    },
    {
      "title": "Ipilimumab and Nivolumab in Patients With Anti-PD-1-axis Therapy-resistant Advanced Non-small Cell Lung Cancer.",
      "url": "https://cdn.clinicaltrials.gov/large-docs/79/NCT03262779/Prot_SAP_000.pdf"
    },
    {
      "title": "REGN2810 (Anti-PD-1 Antibody), Platinum-based Doublet Chemotherapy, and Ipilimumab (Anti-CTLA-4 Antibody) Versus Pembrolizumab Monotherapy in Patients With Lung Cancer",
      "url": "https://cdn.clinicaltrials.gov/large-docs/29/NCT03515629/Prot_000.pdf"
    },
    {
      "title": "Addressing the Elephant in the Immunotherapy Room: Effector T-Cell Priming versus Depletion of Regulatory T-Cells by Anti-CTLA-4 Therapy",
      "url": "https://www.mdpi.com/2072-6694/14/6/1580"
    },
    {
      "title": "The Latest Option: Nivolumab and Relatlimab in Advanced Melanoma",
      "url": "https://link.springer.com/article/10.1007/s11912-023-01406-4"
    },
    {
      "title": "Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904288/"
    },
    {
      "title": "Fc-independent functions of anti-CTLA-4 antibodies contribute to anti-tumor efficacy",
      "url": "https://link.springer.com/article/10.1007/s00262-022-03170-z"
    },
    {
      "title": "(PDF) FcγRIIB Is an Immune Checkpoint Limiting the Activity of Treg-Targeting Antibodies in the Tumor Microenvironment",
      "url": "https://www.researchgate.net/publication/376849296_FcgRIIB_is_an_immune_checkpoint_limiting_the_activity_of_Treg-targeting_antibodies_in_the_tumor_microenvironment"
    },
    {
      "title": "Parenterally administered immune enhancing drugs",
      "url": "https://image-ppubs.uspto.gov/dirsearch-public/print/downloadPdf/12433836"
    },
    {
      "title": "Relatlimab: a novel drug targeting immune checkpoint LAG-3 in melanoma therapy",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10806167/"
    },
    {
      "title": "FDA Approves a Fixed-Dose Combination of Nivolumab and Relatlimab for Unresectable or Metastatic Melanoma",
      "url": "https://www.esmo.org/oncology-news/fda-approves-a-fixed-dose-combination-of-nivolumab-and-relatlimab-for-unresectable-or-metastatic-melanoma"
    },
    {
      "title": "European Commission Approves Nivolumab/Relatlimab Combo for Treatment of Unresectable or Metastatic Melanoma",
      "url": "https://www.cancernetwork.com/view/european-commission-approves-nivolumab-relatlimab-combo-for-treatment-of-unresectable-or-metastatic-melanoma"
    },
    {
      "title": "Nivolumab/Relatlimab Does Not Meet RFS End Point in Stage III/IV Melanoma",
      "url": "https://www.cancernetwork.com/view/nivolumab-relatlimab-does-not-meet-rfs-end-point-in-stage-iii-iv-melanoma"
    },
    {
      "title": "Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects",
      "url": "https://link.springer.com/article/10.1186/s12943-020-01234-1"
    },
    {
      "title": "FcγRIIB Is an Immune Checkpoint Limiting the Activity of Treg-Targeting Antibodies in the Tumor Microenvironment",
      "url": "https://aacrjournals.org/cancerimmunolres/article/12/3/322/734677/Fc-RIIB-Is-an-Immune-Checkpoint-Limiting-the"
    },
    {
      "title": "The 2018 Nobel Prize in Physiology or Medicine - Advanced information: Discovery of cancer therapy by inhibition of negative immune regulation - NobelPrize.org",
      "url": "https://www.nobelprize.org/prizes/medicine/2018/advanced-information/"
    },
    {
      "title": "Revisiting the PD-1 pathway",
      "url": "https://www.science.org/doi/10.1126/sciadv.abd2712"
    },
    {
      "title": "Anti-PD-1 antibodies and uses thereof",
      "url": "https://image-ppubs.uspto.gov/dirsearch-public/print/downloadPdf/10465007"
    },
    {
      "title": "FDA approves new drug for advanced melanoma",
      "url": "https://www.dana-farber.org/newsroom/news-releases/2011/fda-approves-new-drug-for-advanced-melanoma"
    },
    {
      "title": "FDA Approves Ipilimumab for Advanced Melanoma",
      "url": "https://www.medscape.com/viewarticle/739604"
    },
    {
      "title": "How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma - ScienceDirect",
      "url": "https://www.sciencedirect.com/science/article/pii/S0923753419376860"
    },
    {
      "title": "FDA Accepts sBLA for Adjuvant Ipilimumab in Melanoma",
      "url": "https://www.onclive.com/view/fda-accepts-sbla-for-adjuvant-ipilimumab-in-melanoma"
    },
    {
      "title": "The 2018 Nobel Prize in medicine goes to cancer immunotherapy (editorial for BMC cancer)",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231274/"
    },
    {
      "title": "FDA Approves Adjuvant Ipilimumab in Melanoma",
      "url": "https://www.onclive.com/view/fda-approves-adjuvant-ipilimumab-in-melanoma"
    },
    {
      "title": "The 2018 Nobel Prize in Physiology or Medicine - Press release - NobelPrize.org",
      "url": "https://www.nobelprize.org/prizes/medicine/2018/press-release/"
    },
    {
      "title": "Introduction",
      "url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1708873/xml"
    },
    {
      "title": "Nivolumab Alone, With Ipilimumab Demonstrate Sustained 10-Year Survival Benefit in Advanced Melanoma",
      "url": "https://www.onclive.com/view/nivolumab-alone-with-ipilimumab-demonstrate-sustained-10-year-survival-benefit-in-advanced-melanoma"
    },
    {
      "title": "Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma",
      "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2407417"
    },
    {
      "title": "Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma",
      "url": "https://ascopubs.org/doi/10.1200/JCO.2014.56.2736"
    },
    {
      "title": "US Food and Drug Administration Approval Summary: Nivolumab Plus Platinum-Doublet Chemotherapy for the Neoadjuvant Treatment of Patients With Resectable Non–Small-Cell Lung Cancer - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10256356/"
    },
    {
      "title": "Neoadjuvant checkpoint inhibition in non-small cell lung cancer: Is earlier unquestionably better than later? - ScienceDirect",
      "url": "https://www.sciencedirect.com/science/article/pii/S1936523322001644"
    },
    {
      "title": "Efficacy, Safety, and Pharmacodynamics of Tislelizumab Monotherapy and Multiple Tislelizumab-based Immunotherapy Combinations in Participants With Resectable Non-Small Cell Lung Cancer",
      "url": "https://cdn.clinicaltrials.gov/large-docs/02/NCT05577702/Prot_000.pdf"
    },
    {
      "title": "Top advances of the year: Perioperative therapy for lung cancer - Aredo - 2024 - Cancer - Wiley Online Library",
      "url": "https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.35357"
    },
    {
      "title": "Perioperative Immunotherapy for Non-Small Cell Lung Cancer: Practical Application of Emerging Data and New Challenges - ScienceDirect",
      "url": "https://www.sciencedirect.com/science/article/abs/pii/S1525730424000159"
    },
    {
      "title": "Behind the FDA Approval of Neoadjuvant/Adjuvant Pembrolizumab in NSCLC",
      "url": "https://www.targetedonc.com/view/behind-the-fda-approval-of-neoadjuvant-adjuvant-pembrolizumab-in-nsclc"
    },
    {
      "title": "Opdivo + Yervoy Approved as First-Line Tx for MSI-H/dMMR Metastatic Colorectal Cancer",
      "url": "https://www.gastroenterologyadvisor.com/news/opdivo-yervoy-first-line-tx-msi-h-dmmr-colorectal-cancer/"
    },
    {
      "title": "FDA Approves Nivolumab Plus Ipilimumab for dMMR CRC Based on CheckMate-8HW Results",
      "url": "https://www.gioncologynow.com/post/fda-approves-nivolumab-plus-ipilimumab-for-dmmr-crc-based-on-checkmate-8hw-results"
    },
    {
      "title": "FDA Approves Nivolumab/Ipilimumab in Adult/Pediatric MSI-H or dMMR CRC",
      "url": "https://www.cancernetwork.com/view/fda-approves-nivolumab-ipilimumab-in-adult-pediatric-msi-h-or-dmmr-crc"
    },
    {
      "title": "FDA Approves Nivolumab Plus Ipilimumab for dMMR/MSI-H Metastatic CRC",
      "url": "https://www.onclive.com/view/fda-approves-nivolumab-plus-ipilimumab-for-dmmr-msi-h-metastatic-crc"
    },
    {
      "title": "Clinical applications of PD-L1 bioassays for cancer immunotherapy",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436438/"
    },
    {
      "title": "PD-L1 by Immunohistochemistry",
      "url": "https://arupconsult.com/ati/pd-l1-immunohistochemistry"
    },
    {
      "title": "PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy",
      "url": "https://aacrjournals.org/mct/article/14/4/847/91937/PD-L1-Expression-as-a-Predictive-Biomarker-in"
    },
    {
      "title": "PD‐L1 Immunohistochemistry: Clones, Cutoffs and Controversies",
      "url": "https://www.researchgate.net/publication/359459652_PD-L1_Immunohistochemistry_Clones_Cutoffs_and_Controversies"
    },
    {
      "title": "Tissue-agnostic drug approvals: how does this apply to patients with breast cancer?",
      "url": "https://www.nature.com/articles/s41523-021-00328-3"
    },
    {
      "title": "FDA Approval Summary: Pembrolizumab for the treatment of tumor mutational burden-high solid tumors - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8416776/"
    },
    {
      "title": "Full article: Tumor mutational burden as a tissue-agnostic biomarker for cancer immunotherapy",
      "url": "https://doi.org/10.1080/17512433.2021.1865797"
    },
    {
      "title": "Broader gene representation by whole-exome sequencing improves accuracy of tumor mutational burden assessment for selection of pembrolizumab immunotherapy - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13161441/"
    },
    {
      "title": "Real-World Pseudoprogression: an Uncommon Phenomenon - Journal of Thoracic Oncology",
      "url": "https://www.jto.org/article/S1556-0864(18)30612-9/fulltext"
    },
    {
      "title": "Atypical patterns of response to immune checkpoint inhibitors: interpreting pseudoprogression and hyperprogression in decision making for patients’ treatment - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6384391/"
    },
    {
      "title": "[iRECIST: assessment of immunotherapy response] - PubMed",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41498990/"
    },
    {
      "title": "Utility of iRECIST for evaluating treatment efficacy in patients receiving immune checkpoint inhibitors - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13226079/"
    },
    {
      "title": "Optimizing the clinical assessment of pseudoprogression in patients with solid tumors treated with checkpoint inhibitors: a systematic literature review and meta-analysis of associated features - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13264642/"
    },
    {
      "title": "A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases",
      "url": "https://www.nature.com/articles/s41379-020-00664-y"
    },
    {
      "title": "PD-L1 testing by immunohistochemistry in immuno-oncology",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9901897/"
    },
    {
      "title": "Biomarker and companion diagnostic testing  - Insights",
      "url": "https://news.mayocliniclabs.com/pathology/biomarker-and-companion-diagnostic-testing/"
    },
    {
      "title": "The Role of Histology-Agnostic Drugs in the Treatment of Metastatic Castration-Resistant Prostate Cancer",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9369092/"
    },
    {
      "title": "Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?",
      "url": "https://academic.oup.com/oncolo/article/25/2/94/6443054"
    },
    {
      "title": "The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277892/"
    },
    {
      "title": "Mechanisms of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Patients with Hepatocellular Carcinoma",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9564277/"
    },
    {
      "title": "Mechanisms of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Patients with Hepatocellular Carcinoma - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9564277/"
    },
    {
      "title": "Resistance mechanisms to immune checkpoint inhibitors: updated insights",
      "url": "https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02212-7"
    },
    {
      "title": "Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma",
      "url": "https://aacrjournals.org/clincancerres/article/24/6/1260/468/Primary-and-Acquired-Resistance-to-Immune"
    },
    {
      "title": "(PDF) Compensatory upregulation of PD-1, LAG-3 and CTLA-4 limits the efficacy of single agent checkpoint blockade in metastatic ovarian cancer",
      "url": "https://www.researchgate.net/publication/309542734_Compensatory_upregulation_of_PD-1_LAG-3_and_CTLA-4_limits_the_efficacy_of_single_agent_checkpoint_blockade_in_metastatic_ovarian_cancer"
    },
    {
      "title": "PD-1 blockade upregulate TIM-3 expression as a compensatory regulation of immune check point receptors in HNSCC TIL",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649333/"
    },
    {
      "title": "Full article: Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer",
      "url": "https://www.tandfonline.com/doi/full/10.1080/2162402X.2016.1249561"
    },
    {
      "title": "Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer - PubMed",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28197389/"
    },
    {
      "title": "Study of Retinfanlimab in Combination With INCAGN02385 and INCAGN02390 as First-Line Treatment in Participants With PD-L1-Positive (CPS ≥ 1) Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck",
      "url": "https://cdn.clinicaltrials.gov/large-docs/13/NCT05287113/Prot_000.pdf"
    },
    {
      "title": "Frontiers",
      "url": "https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.641428/full"
    },
    {
      "title": "From immune exclusion to exhaustion: tumor microenvironment drives therapy response - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13144129/"
    },
    {
      "title": "Resistance to immune checkpoint therapies by tumour-induced T-cell desertification and exclusion: key mechanisms, prognostication and new therapeutic opportunities",
      "url": "https://www.nature.com/articles/s41416-023-02361-4"
    },
    {
      "title": "Tumor Microenvironment: T Cell Exclusion: R&D Systems",
      "url": "https://www.rndsystems.com/research-area/immuno-oncology/tumor-microenvironment/t-cell-exclusion"
    },
    {
      "title": "Precision cytokine modulation to overcome tumor microenvironment-driven resistance to immune checkpoint blockade - ScienceDirect",
      "url": "https://www.sciencedirect.com/science/article/pii/S0304419X26000089"
    },
    {
      "title": "Resistance to immune checkpoint therapies by tumour-induced T-cell desertification and exclusion: key mechanisms, prognostication and new therapeutic opportunities",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10575907/"
    },
    {
      "title": "Genomic and molecular alterations associated with primary resistance to immune checkpoint inhibitors",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11399531/"
    },
    {
      "title": "Primary and acquired resistance mechanisms to immune checkpoint inhibition in Hodgkin lymphoma - Cancer Treatment Reviews",
      "url": "https://www.cancertreatmentreviews.com/article/S0305-7372(19)30152-5/fulltext"
    },
    {
      "title": "Tumor microenvironment-driven resistance to immunotherapy in non-small cell lung cancer: strategies for Cold-to-Hot tumor transformation",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12059482/"
    },
    {
      "title": "Immune-related adverse events of immune checkpoint inhibitors: a review",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10247998/"
    },
    {
      "title": "Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitors: A Scoping Review",
      "url": "https://www.mdpi.com/1424-8247/19/2/276"
    },
    {
      "title": "Nivolumab Plus Relatlimab or Ipilimumab in Metastatic Melanoma Stratified by MHC-II Expression",
      "url": "https://cdn.clinicaltrials.gov/large-docs/68/NCT03724968/Prot_SAP_000.pdf"
    },
    {
      "title": "Frontiers",
      "url": "https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1187840/full"
    },
    {
      "title": "Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis",
      "url": "https://link.springer.com/article/10.1186/s12916-015-0455-8"
    },
    {
      "title": "Cutaneous adverse events in patients treated with PD-1/PD-L1 checkpoint inhibitors and their association with survival: a systematic review and meta-analysis",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9681870/"
    },
    {
      "title": "Association between Early Immune-Related Adverse Events and Survival in Patients Treated with PD-1/PD-L1 Inhibitors",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917734/"
    },
    {
      "title": "Immune-related adverse events with cancer clinical benefits: a systematic review and meta-analysis - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13584344"
    },
    {
      "title": "Checkpoint inhibitor immune-related adverse events: A focused review on autoantibodies and B cells as biomarkers, advancements and future possibilities",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9874109/"
    },
    {
      "title": "Personalized Immunotherapy in Patients With Recurrent /Metastatic SCCHN That Have Progressed on Prior Immunotherapy",
      "url": "https://cdn.clinicaltrials.gov/large-docs/57/NCT04326257/Prot_SAP_000.pdf"
    },
    {
      "title": "Meta-Analysis of the Risk of Immune-Related Adverse Events With Anticytotoxic T-Lymphocyte-Associated Antigen 4 and Antiprogrammed Death 1 Therapies - PubMed",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28118483"
    },
    {
      "title": "Clinical guideline highlights for the hospitalist: Management of immune‐related adverse events in patients treated with immune checkpoint inhibitor therapy - Chitnis - 2023 - Journal of Hospital Medicine - Wiley Online Library",
      "url": "https://shmpublications.onlinelibrary.wiley.com/doi/full/10.1002/jhm.13097"
    },
    {
      "title": "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update",
      "url": "https://ascopubs.org/doi/10.1200/JCO.21.01440"
    },
    {
      "title": "Steroids in Immune Checkpoint Inhibitor Myocarditis",
      "url": "https://www.jacc.org/doi/10.1016/j.jaccao.2024.07.002"
    },
    {
      "title": "(PDF) Management of infliximab refractory immune checkpoint inhibitor gastrointestinal toxicity: a multicenter case series",
      "url": "https://www.researchgate.net/publication/377864046_Management_of_infliximab_refractory_immune_checkpoint_inhibitor_gastrointestinal_toxicity_a_multicenter_case_series"
    },
    {
      "title": "Vedolizumab Attenuates Immune-Checkpoint-Therapy-Induced Infliximab-Refractory Colitis",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870896/"
    },
    {
      "title": "Efficacy of Infliximab Versus Vedolizumab in the Management of Immune Checkpoint Inhibitor-Induced Colitis: A Systematic Review and Meta-Analysis - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12339259"
    },
    {
      "title": "Calcineurin inhibitors in steroid and anti‐TNF‐alpha refractory immune checkpoint inhibitor colitis - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8114988/"
    },
    {
      "title": "Therapeutic agents for steroid-refractory immune checkpoint inhibitor-related myocarditis: a narrative review - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC11384453/"
    },
    {
      "title": "Steroid-Refractory Immune-Related Adverse Events Induced by Checkpoint Inhibitors - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10177379/"
    },
    {
      "title": "Therapeutic agents for steroid-refractory immune checkpoint inhibitor-related myocarditis: a narrative review - Wang - Cardiovascular Diagnosis and Therapy",
      "url": "https://cdt.amegroups.org/article/view/127481/html"
    },
    {
      "title": "The ASCO Post",
      "url": "https://ascopost.com/News/58570"
    },
    {
      "title": "Immune Checkpoint Inhibitor Rechallenge After Immune-Related Adverse Events in Patients With Cancer",
      "url": "https://jamanetwork.com/journals/jamaoncology/fullarticle/2764543"
    },
    {
      "title": "Efficacy and safety of immune checkpoint inhibitor rechallenge following immune-related adverse events: a review",
      "url": "https://academic.oup.com/jjco/article/56/2/117/8379487"
    },
    {
      "title": "Recurrence of Immune-Related Adverse Events After Checkpoint Inhibitor Rechallenge in Patients With Cancer",
      "url": "https://ascopost.com/issues/may-25-2020/recurrence-of-iraes-after-checkpoint-inhibitor-rechallenge-in-patients-with-cancer/"
    },
    {
      "title": "Immune Checkpoint Inhibitor Rechallenge After Prior Immune Toxicity - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9402751/"
    },
    {
      "title": "Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234197/"
    },
    {
      "title": "Oncolytic Viruses and Immune Checkpoint Inhibition: The Best of Both Worlds: Molecular Therapy - Oncolytics",
      "url": "https://www.cell.com/molecular-therapy-family/oncology/fulltext/S2372-7705(19)30051-8"
    },
    {
      "title": "Immune Checkpoint Inhibitors Combined with Oncolytic Virotherapy: Synergy, Heterogeneity, and Safety in Cancer Treatment",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12712690/"
    },
    {
      "title": "Durable Response Following the Discontinuation of Immune Checkpoint Inhibitor Therapy in Advanced Non-small Cell Lung Cancer",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141771/"
    },
    {
      "title": "Long-term immune checkpoint inhibitor therapy in a patient with metastatic nasopharyngeal carcinoma: a case report",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198176/"
    },
    {
      "title": "Combination immunotherapy with oncolytic vaccinia virus and checkpoint inhibitor following local tumor irradiation",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288403/"
    },
    {
      "title": "Discontinuation of immune checkpoint inhibitor (ICI) above 18 months of treatment in real-life patients with non-small cell lung cancer (NSCLC): INTEPI, a multicentric retrospective study.",
      "url": "https://ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.9082"
    },
    {
      "title": "Early discontinuation of immune checkpoint inhibitor therapy prior to disease progression in patients with metastatic non-small cell lung cancer: a survival analysis - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC11224446/"
    },
    {
      "title": "Study Details",
      "url": "https://clinicaltrials.gov/study/NCT04637594"
    },
    {
      "title": "Effectiveness of Immune Checkpoint Inhibitors in Various Tumor Types Treated by Low, Per-Weight, and Conventional Doses at a Tertiary Care Center in Mumbai",
      "url": "https://ascopubs.org/doi/10.1200/GO.23.00312"
    },
    {
      "title": "Modelling the potential financial impacts of expanding access to immune checkpoint inhibitors as monotherapy for treating advanced non-small cell lung cancer",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159930/"
    },
    {
      "title": "A call to action: improving access to cardiac MRI for diagnosis of immune checkpoint inhibitor related myocarditis in low and middle income countries",
      "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12574015/"
    },
    {
      "title": "Journal of Cancer 2025, Vol. 16 https://www.jcancer.org 1782 Journal of Cancer",
      "url": "https://www.jcancer.org/v16p1782.pdf"
    },
    {
      "title": "Availability, Prices, and Affordability of Immune Checkpoint Inhibitors: A Cross-Sectional Study in Anhui Province, China",
      "url": "https://link.springer.com/article/10.1007/s41669-026-00658-7"
    },
    {
      "title": "Barriers to Immune Checkpoint Inhibitor Access for Patients With Cancer in Southeast Asia: Challenges and Policy Implications - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12373009/"
    },
    {
      "title": "Use of low-dose immune checkpoint inhibitors in low- and middle-income countries: a national survey of oncologists and hematologists in Mexico - PMC",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13354815/"
    }
  ],
  "license": "https://creativecommons.org/licenses/by/4.0/"
}